The mechanisms of assembly and function for many important type I/II (single-pass) transmembrane (TM) receptors are proposed to involve the formation and/or alteration of specific interfaces among their membrane-embedded alpha-helical TM domains. What these intramembrane interfaces look like and how they gain specificity is only poorly understood because of substantial technical challenges regarding their structural and functional characterisation. Isolated TM fragments are generally considered poor candidates for crystallisation due to their high hydrophobicity, flexible non-helical flanking sequences, low abundance of potential crystal contacts and the requirement for high lipid or detergent content in samples for screening. However, our lab has recently determined structures of TM complexes derived from glycophorin A1 and the immunoreceptor signalling adaptor DAP122 in monoolein lipidic cubic phase (LCP), demonstrating that TM complexes can be crystallised in a lipid bilayer and that native TM helix-helix interfaces are faithfully recapitulated under these conditions3. Since this provides compelling support for the wider application of LCP media for structural analysis of small TM complexes, we are currently using the technique in combination with LCP-FRAP (Fluorescence Recovery After Photobleaching) analysis to obtain structural information about other cell-surface receptors and related regulatory proteins that act via TM helix‑helix interactions. To complement structural studies, we further established Deep Mutational Scanning analysis of TM segments as a high‑throughput method to obtain mutational landscapes that characterise such interactions in great detail.